The tetracycline compound, 7-dimethylamino-6-deoxy-6-demethyltetracycline, and its non-toxic acid addition salts are widely used in therapy primarily for their antimicrobial effects. Commonly assigned Boothe et al, U.S. Pat. Nos. 3,148,212, and Pesti et al, 3,226,436, describe the preparation of minocycline. Although the compounds have achieved widespread use in oral dosage forms, they have several drawbacks.
The minimum therapeutically effective blood serum or plasma concentration level of minocycline in a human subject varies according to the organism causing the infection. The concentration is determined in vivo by clinical evaluation and in vitro by microbiological assays. Currently, the minimum therapeutically effective concentration is believed to be in the range of from about 0.1 to about 1.0 mcg of minocycline/ml of serum.
Organisms currently known to be susceptible to minocycline therapy include a wide range of gram-negative and gram-positive bacteria including, but not limited to agents of rickettsiae (Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, tick fevers); Mycoplasma pneumoniae (PPLO, Eaton agent); agents of psittacosis and ornithosis; agents of lymphogranuloma venereum and granuloma inguinale; the spirochetal agent of relapsing fever (Borrelia recurrentis); the agent of Lyme disease (Borrelia burgdorfeni), the agents of acne (Propionibacterium Corynebacterium acnes); the microorganisms Haemopnilus ducreyi(chancroid), Yersinia pestis and Francisella tularensis, formerly Pasteurella pestis and Pasteurella tularensis, Bartonella bacilliformis, Bacteroides species, Vibrio comma and Vibrio fetus, Brucella species, Escherichia coli, Enterbacter aerogenes (formerly Aerobacter aerogenes), Shigella species, Mima species, Herellea species, Haemophilus influenzae (respiratory infections), Klebsiella species (respiratory and urinary infections), many Streptococcus species including strains of Streptococcus pyogenes and Streptococcus faecalis, Streptococcus pneumoniae, Staphylococcus aureus (skin and soft tissue infections), Neisseria gonorrhoeae, Neisseria meningitidis, Treponema pallidum and Treponema pertenue (syphilis and yaws), Listeria monocytogenes, Clostridium species, Bacillus anthracis, Fusobacterium fusiforme (Vincent's infection), Actinomyces species; and in the treatment of acute intestinal amebiasis and inclusion conjunctivitis. Physician's Desk Reference, 1987, Medical Economics Company, Oradell, N.J.(PDR 43rd Ed.).
Recent discovery shows that minocycline is absorbed at different rates in different portions of the gastrointestinal tract. Intubation studies in human patients have demonstrated that bioavailability of minocycline in the gastrointestinal tract, based upon 100 percent absorption in the stomach, is 106 percent in the duodenum, 80 percent in the jejunum and 58 percent in the ileum, indicating that minocycline demonstrates reduced absorption in the lower gastrointestinal tract.
The human stomach empties in about one hour in a fasting subject and in about one to about four hours with food. The half life of minocycline when taken without food is approximately 10 hours. When taken with food, the half life is extended to approximately 14 to 16 hours.
It has not been possible to achieve a once-a-day therapeutic blood level of minocycline using only delayed release granules of minocycline with or without food ingestion. Traditional pharmaceutical forms and traditional delayed release forms containing minocycline require frequent ingestion of multiple doses per day resulting in wide variations in serum concentration throughout the course of treatment and in poor patient compliance. This indicates a need for a custom designed once-a-day delivery system for minocycline to provide optimal therapeutic effect and patient compliance.
Shepard, U.S. Pat. No. 3,080,294, discloses a sustained release pharmaceutical tablet comprising an inner core coated with multiple layers of an active medicament mixture, each layer releasing a portion of active medicament as it is successively dissolved. Such layers are not pH adapted, however.
Amann, U.S. Pat. No. 3,865,935, discloses erythromycin tablets which are stable outside the stomach but which produce immediate action upon disintegration in the stomach. These tablets require sodium citrate or sodium citrate dihydrate and do not yield a controlled release of prolonged duration.
McAinsh et al, U.S. Pat. No. 4,138,475, disclose that propranolol or a pharmaceutically acceptable salt thereof can be formulated into a sustained release pharmaceutical composition by mixing with a non-water-swellable microcrystalline cellulose and forming into spheroids. These spheres are coated with a heavy film of hydroxypropyl methylcellulose and/or a plasticizer to eliminate any release of the drug in the stomach. The film coated spheroids are then filled into gelatin capsules. Apart from the fact that propranolol is used as a beta-blocker to treat heart problems and not for oral antimicrobial use, there is no hint or suggestion in McAinsh et al that the pharmaceutical compositions should be used with tetracycline compounds.
Dempski, et al, U.S. Pat. No. 4,173,626, disclose capsules comprising uncoated indomethacin (U.S. Pat. No. 3,161,654) pellets for immediate release, coated indomethacin pellets for prolonged release, and non-medicated pellets as volume fill. Indomethacin is a prostaglandin synthetase inhibitor and is not an antibacterial agent. Furthermore, the coatings are not pH adapted.
Hess, et al, U.S. Pat. No. 4,353,887, disclose a divisible tablet comprising medicament containing granules wherein the surface area of the tablet is not materially increased by division.
In Bechgaard, U.S. Pat. No. 4,606,909, the placement of a sparingly soluble active substance, such as tetracycline, in an oral controlled release dosage form is disclosed. The sparingly soluble active substance must be used with a dispersion-enhancing substance, such as an anionic detergent, to promote solubility in intestinal fluids. The composition is formed into small spheres and enteric coated to eliminate any release of drug in the stomach. The coated spheres are tabletted or loaded into capsules. There is no teaching that such a dosage form can be used to provide a once-a-day delivery system of therapeutically effective amounts of 7-dimethylamino-6-deoxy-6-demethyltetracycline or its non-toxic acid addition salts, and particularly a delivery system which is not dependent upon the ingestion of food. Moreover, the requirement of a dispersion-enhancing substance, especially an anionic detergent, is a negative factor.
In Ventouras, U.S. Pat. No. 4,784,858, a controlled release tablet comprising (1) coated cores, not necessarily spheronized, comprising a core of a water-soluble pharmaceutically active substance dispersed in a water-insoluble polymeric excipient and a swellable water-insoluble polymeric substance; and (2) a coating of an elastic, water insoluble and semi-permeable diffusion film of a polymer is disclosed. Here, the core is made to expand with water, causing the surface of the coating to extend, making it permeable, and thereby releasing the medicament in the core.
U.K. Patent Publication No. GB 2,041,222 discloses the tabletting of microcapsules of indoprofen, Other active medicaments may be included in the tablet. The microcapsules are not formed by spheronization, and these tablets are only suitable for or high dosage delivery.
The incorporation of water insoluble medicament containing spheroids comprised of microcrystalline cellulose and at least one cellulose derivative into capsules, sachets, and cachets is disclosed in U.K. Patent Publication No. GB 2,202,143. Sustained released is accomplished by the necessary inclusion of the cellulose derivative.
Parke-Davis has recently offered for use by the medical profession, capsules under the trademark DORYX.RTM. containing specially coated pellets of doxycycline hyclate for oral administration. See, PDR 43rd Ed. (Pages 1487-1489). In contrast to minocycline hydrochloride and its isomers and analogs, doxycycline hyclate does not contain an alkyl amino group at either the 7- or the 9-position. The Parke-Davis pellets are said to comprise lactose, microcrystalline cellulose and povidone (polyvinylpyrrolidone) in addition to the doxycycline compound. The disclosure in PDR 43rd Ed. is unclear as to the advantages for using such film coated pellets, but it is believed that the film is used to minimize release in the stomach and any resulting gastric distress and not to provide a once-a-day dosage form.
Valorose et al, U.S. Pat. No. 4,837,030, disclose hard gelatin or soft gelatin capsules filled with minocycline comprising spherical granules.
Concurrently filed, copending U.S. patent application Ser. No. 07/410,707 abandoned, discloses tablets comprising active spherical granules containing medicaments including tetracycline compounds and compressible spherical granules.
Concurrently filed, copending U.S. Patent application Ser. No. 07/410,709 abandoned, discloses hard shell and soft shell capsules filled with carbonic anhydrase inhibitor containing spherical granules.
It has now been discovered that a specific minocycline composition can be formulated to provide at least minimum therapeutic serum levels of the minocycline in a human subject for about 24 hours through once-a-day two pulse administration systems, comprising an initial loading component providing the first pulse which is absorbed up to 100 percent in the stomach and a secondary loading component providing the second pulse which is absorbed up to 100 percent in the duodenum and the upper part of the small intestine.
These formulations can also be processed into liquid, capsule, or tablet oral dosage unit forms.